Hormones

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Hormones Hormone AntagonistsChapter 40 -
Katzung

• Least toxic of anticancer drugs
• Highly selective
• Breast, endometrial, prostate cancers
• 5 Categories
• Androgens Progestins
• Antiandrogens
• Gonadotropin-releasing hormone analogs
• Estrogens Antiestrogens
• Aromatase inhibitors

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Hormone Synthesis
Progesterone
Aromatase
Aromatase
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Androgens Breast cancer
Indications palliative therapy in advanced
disseminated breast cancer MOA irreversible
inhibitor of the enzyme steroid aromatase that is
responsible for the synthesis of estrone from
androstenedione Hepatic metabolism,
contraindicated in male breast cancer

• Most commonly used androgen for breast cancer.
• Few or no androgenic side effects - hirsutism
• Adrenal estrogen depletion post menopausal
  women

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Progestins - endometrium
Indications palliative treatment of carcinoma
of the breast or endometrium off-label use
appetitie stimulant in HIV Not recommended during
the first 4 months of pregnancy, must use at
least 2 months of therapy to determine
efficacy MOA Anti-leutinizing effect mediated
by the pituitary gland and marked changes in
progestatinal agent movement into the
endometrium Marked weight gain, thromboembolisms,
USE contraception
Indications adjunctive and palliative treatment
of inoperable metastatic recurrent endometrial
cancer, advanced breast cancer and renal
carcinoma, Other long acting contraceptive via
IM injection MOA inhibits secretion of
pituitary gonadotropin which prevents follicular
maturation and ovulation, converts proliferative
endometrium into secretory endometrium May cause
hepatic failure, avoid use in first 4 months of
pregnancy, thromboembolism
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Anti-Androgens - prostate
Indications metastatic carcinoma of the
prostate MOA non-steroidal anti-androgen
inhibits cellular uptake of androgen steroids and
inhibits nuclear binding of androgens to their
receptors - adrenal Used with LHRH (GnRH)
agonists, photosensitivity, inform patients of
urine color changes, hepatic metabolism with
renal excretion, 96 protein bound Indications
For use in combo treatment with surgical
castration for metastatic carcinoma of the
prostate MOA non-steroidal anti-androgen that
inhibits cellular uptake of testosterone and
inhibits nuclear binding to its receptor -
adrenal Hepatic metabolism of methyl group
produces two enantiomers in which one is major
pcol active compound Inhibits a variety of CYP
enzymes, inform patients of night adaptation
problems
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Anti-Androgens - prostate
Indications Advanced prostate cancer MOA a
non-steroidal competitive inhibitor of the
cytosolic androgen receptors - adrenal Prostatic
carcinoma is androgen sensitive Mixture of
enantiomers - stereospecific metabolism occurs
R-enantiomer of the drug is predominate serum
drug Drug must be taken in combination with
luteinizing-hormone releasing hormone (LHRH)
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GnRH Agonists - prostate

• Gonadotropin-releasing hormone (GnRH)
• GnRH released from the hypothalamus
• Signals pituitary gland
• Agonists
• Suppress testicular androgen production
• Negative feedback inhibitor
• Chemical Castration!

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GnRH Agonists cont

• Leuprolide (Lupron)
• Synthetic analog of GnRH
• Decreased androgen production in testes
• SC or IM (q month, q 3 months)
• Titanium implant (Viadur Duros)
• Polymeric dosing (Eligard) every 3 months
• Palliative Advanced prostate carcinoma
• Doesnt decrease adrenal androgens
• Add Flutamide!
• Loss of libido, impotence
• Gosarelin (Zoladex)
• SC pellet ? upper abdomen

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Estrogens - prostate
Indications inoperable prostate cancer Absolute
contraindication in women MOA Non-steroidal
estrogen that binds to cytosolic estrogen
receptor with the complex being transported to
the nucleus where androgenic activity is
antagonized by receptor competition Primary
hepatic metabolism with conjugated renally
excreted Contraindicated in men with cancer of
the breast, any estrogen dependent neoplasm,
thromboembolitic disorders Previously discussed
prostatic carcinoma prodrug containing a mustard
alkylating groups
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Antiestrogens

• Block estrogen receptors
• Breast cancer ONLY!
• All estrogen agonist/antagonists
• Selective Estrogen Receptor Modulators
• SERMs

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Antiestrogens cont

• Tamoxifen (Nolvadex)
• Most widely Rx for breast cancer (DOC)!
• P.O.
• Used to
• Treat existing disease
• Prophylaxis (high risk)
• Post-surgery adjunct therapy
• Estrogen stimulates tumor growth
• Blocks tumor estrogen receptors
• Tumor must be receptor

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Tamoxifen cont

• Receptor deactivation can
• Increase bone density
• Reduce LDL levels bad lipids
• Increase HDL levels good lipids
• Increase cancer risk
• Endometrial carcinoma
• Thromboembolism
• Typical dose 20 mg p.o. q.d.

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Antiestrogens
Indications Adjunctive treatment of breast
cancer, prevention of breast cancer in
genetically predisposed women and men MOA
non-steroidal anti-estrogen that competes with
estradiol for estrogen receptors in target breast
tissues Hepatic metabolism to conjugates that are
renally excreted, hepatic failure possible,
thromboembolism especially PEs, have regular
gynecologic exams, use only non-hormonal
contraceptive methods Indications Breast cancer
( ER or unknown) MOA same as
above Extensively metabolized by CYP3A4,
extensive enterohepatic recirculation Watch for
thromboembolism, leukopenia, may cause
endometrial hyperplasia, patients with metastatic
bone lesions may suffer hypercalcemia, if vaginal
bleeding occurs immediately contact MD
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Antiestrogens
Indications Adjunctive treatment of breast
cancer Approved April 2002 Intramuscular
injection only given once monthly 250 mg MOA
Steroidal estrogen antagonist that competes with
estradiol for estrogen receptors in target breast
cancer tissues down regulates the estrogen
receptor protein present in human breast cancer
cells - appears active against tamoxifen-resistant
cell lines No estrogen agonist activity Highly
protein bound to plasma protein including VLDL,
LDL and HDL Metabolism is primary CYP3A4 and some
non-CYP450 processes with elimination 90
hepatobiliary No known drug interactions to date
other than possible CYP3A4 inducer effects
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Aromatase Inhibitors

• Breast cancer drug class!!!
• Target post-menopausal women
• Blocks estrogen production (androgens)
• Does NOT block ovarian production!

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Aromatase Inhibitors
Progesterone
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Aromatase Inhibitors

• Anastrozole (Arimidex)
• Gold Standard!
• Used when Tamoxifen fails
• Not effective for ER- tumors!
• As effective as Tamoxifen, fewer side-effects
• No apparent endometrial cancer risk!
• Letrozole (Femara)
• Exemestane (Aromasin)

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Aromatase Inhibitors

• Indications Advanced breast cancer not
  responding to tamoxifen therapy exemestrane is
  also used to prevent prostate cancer, Anastrozole
  adjunct for breast cancer (new 2002)
• MOA inhibitors of the enzyme aromatase that
  is responsible for the conversion of adrenally
  produced androstenedione to estradiol - no effect
  on aldosterone synthesis
• Letrozole and Anastrozole are reversible
  competitive inhibitors
• Exemestrane is an irreversible inhibitor (suicide
  substrate)
• Use caution in patients with hepatic and renal
  impairment
• Anastrozole inhibits CYP 1A2, 2C8/9 and 3A4 at
  high dosages

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Summary Hormone Drugs